The compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b ][1,5]benzodiazepine [olanzapine] is useful for treating-psychotic patients and mild anxiety states. Preparation of olanzapine and its acid salts having pharmaceutical properties particularly in the treatment of central nervous system disorders has been disclosed in U.S. Pat. No. 5,229,382 (hereinafter referred to as the '382 patent). This patent does not refer to any specific polymorphic crystalline form of olanzapine.
Olanzapine exists in two important polymorphic forms, known as Form I and Form II, distinguishable by X-ray powder diffractrometry. EP 733,635 claims Form II of olanzapine and designates the product obtained according to the process described in previous the '382 patent as Form I. It also describes the preparation of Form II olanzapine from ethyl acetate. This patent further adds that anhydrous Form I of olanzapine is metastable and is therefore not well suited for commercial use in pharmaceutical formulations.
However, it has been discovered that anhydrous Form I olanzapine, is stable and is therefore well adapted for commercial use in pharmaceutical formulations. Accordingly there is a need for a process to prepare olanzapine Form I free from the Form II impurity. It is desirable to prepare the substantially pure anhydrous Form I olanzapine to assure uniformity of product.
Although example 1 of the '382 patent discloses a process to obtain olanzapine Form I by recrystallization of olanzapine from acetonitrile, the polymorphic form in these experiments was characterized for its X-ray Powder diffraction and showed that the d values for this product matched with those of olanzapine Form II claimed in EP 733,635. It is therefore inferred that recrystallization of Olanzpine in acetonitrile produces form II and not Form I.
WO 02/18390 discloses a process for the preparation of form I of olanzapine by crystallization of raw olanzapine, olanzapine hydrate or its polymorphic form II from methylene chloride. It has been found that extending the duration of the process of olanzapine crystallization from methylene chloride to yield sufficiently pure final crystalline form I leads to the formation of the additional contaminating compound, especially during heating at reflux temperature. Also repeated crystallization from methylene chloride lead only to a progressive accumulation of the impurity to levels unacceptable in view of the purity requirements for the pharmaceutical materials.
WO03101997 A1 [equivalent to US 2004/0048854 A1] discloses a process of preparation of Form I olanzapine free of the Form II impurity. According to this patent olanzapine is purified in an acidic medium followed by extraction with organic solvents. The resulting mixture is then basified under cold conditions and then extracted using low boiling organic solvents. Further, it discloses that a basic solvent (such as toluene and methanolic sodium hydroxide) is critical to separate out Olanzapine Form I.
WO 03/055438 discloses a process of seeding a solution of an alcoholic solution with substantially pure form I, prior to crystallization to obtain Form I as a product.
Until now, there has been no disclosure of obtaining Olanzapine Form I by precipitation, which generally is a much more simpler technique. Thereby, the inventors of the present application have discovered a novel method for obtaining substantially pure Olanzapine Form I by precipitation technique.
The present invention related to a process for preparation of substantially pure Olanzapine Form I. The polymorphic Form I herein represents the Form I as defined in EP 733,635 and WO96/30375. The X-ray diffractogram of this polymorphic form exhibits the characteristic inter-planar distances d (in angstroms): 9.94, 8.55, 8.24, 6.88, 6.24, 5.58, 5.30, 4.98, 4.83, 4.72, 4.62, 4.53, 4.46, 4.29, 4.23, 4.08, 3.82, 3.74, 3.69, 3.58, 3.50, 3.33, 3.28, 3.21, 3.11, 3.05, 2.94, 2.81, 2.75, 2.65, 2.63, 2.59.